Disorders of cognition are generally accompanied by symptoms of forgetfulness, confusion, memory loss, and other aspects as a result of aging, brain injury or disease. The concomitant decrease in cognitive function during the aging process has been documented in various mammals and more recently in human subjects as well. In particular, presenile and senile primary degenerative dementia appear to be common causes of mental deterioration among the elderly. In fact, the symptoms of cognitive disorder appear to be associated with decreased acetyl chlorine synthesis as well as impairment of the choline receptive neurons. Especially, the activity of the enzyme choline acetyl transferase (CAT) which catalyzes the synthesis of acetyl choline from its previous choline and acetyl coenzyme A can be severely reduced as reflected by the loss of cholinergic (acetyl choline releasing) nerve ending in the hippocampus. The cholinergic terminals are recognized as critically important to memory function.
The alkaloid arecoline (methyl ester of 1-methyl-1,2,5,6-tetrahydropiperidine-3-carboxylic acid) which is isolated from betel nuts is well-known as to its mucscarinic effects. However, arecoline is toxic to mammals and therefore limited to veterinary anthelmintic use. Certain alkaloid derivatives, such as O-substituted 1,2,5,6,-tetrahydropyridine oximes, have shown pharmacological properties useful for therapy of age-associated memory impairment and primary degenerative dementia. In particular, the drug CI-979 has been described, inter alia, in U.S. Pat. No. 4,786,648, which disclosure is incorporated herein by reference, as a cognition activator presently under development for the treatment of Alzheimer's disease.
The compound CI-979 HCl has the following structural formula (Ia) ##STR1##
As can be seen from formula (Ia), CI-979 contains a methyloxime group attached to a basic tetrahydropyridine ring to form 1,2,5,6-tetrahydro-1-methyl-3-pyridine carboxaldehyde O-methyloxime. Similar to other pyridine derivatives, the free base form, CI-979, is an oily liquid which is volatile, whereas the CI-979 monohydrochloride is a stable white crystalline salt having a m.p. of 218.degree.-219.degree. C.
The storage stability of the drug has been tested by exposure to heat, UV light, and the extremes of the pH range. While the CI-979 HCl bulk drug is stable for at least six weeks at high temperature and high humidity, it was found that under similar storage conditions a significant drug loss recurred from some solid formulations. In particular, results from excipient compatibility studies show that the HCl salt converts to the volatile free base in the presence of a basic or neutral solid excipient and may, consequently, be lost from the solid composition by evaporation.
Conversely, in acidic environments of less than about pH 5, the drug has been found to undergo hydrolysis, thereby forming an aldehyde degradation product (A) which is biologically inactive.
Two major degradation pathways have been proposed for CI-979 HCl. One pathway represents the hydrolysis to the aldehyde compound (A), 1,2,5,6-tetrahydro-1-methyl-3-pyridine carboxaldehyde, under acidic (i.e. &lt;pH 5) conditions. The second pathway consists of isomerization to the syn- (or Z-) isomer of CI-979 by exposure to UV light.
In particular, hydrolysis of CI-979 to the aldehyde form is a temperature dependent first-order reaction. The light-catalyzed reaction of CI-979 HCl in solution is apparently somewhat pH-dependent, with the highest rate of isomerization occurring at about pH 8.0. The UV light energy presumably weakens the oxime double bond and potentiates rotation to a thermodynamically less stable state.
Moreover, the alkaloid drug, CI-979 HCl, has been found to be labile in acidic or neutral, only slightly humid microenvironment, even in the solid state, a microenvironment being defined as the ambient conditions surrounding a given molecular aggregate or agglomerate. In fact, CI-979 HCl undergoes hydrolysis as a solid mixture formulated in bulk with polyhydroxy excipients. However, only minimal isomerization has been observed as measured by reverse phase high performance liquid chromatography.
Consequently, the storage stability problem of the drug as a solid formulation represented a two-fold dilemma. On the one hand, an acid microenvironment would cause hydrolysis of CI-979 HCl, although prevent conversion of the HCl-salt to the free base and subsequent volatilization. On the other hand, an alkaline microenvironment would diminish CI-979 degradation but allow formation of the volatile free base of the drug.
It is well-known to the skilled in the art that cyclic polydextrose molecules such as cyclodextrin and derivatives thereof, tend to entrap other, smaller molecules thereby endowing such trapped molecules with certain new physicochemical or pharmacotechnical properties. For example cyclodextrins can be used to stabilize certain liquids or oils by effecting their transformation into solid forms or stabilize products susceptible to oxidation, evaporation, or other reactions in air, light or heat. Cyclodextrins are also known to stabilize some products susceptible to hydrolysis. Generally, however, the main utility of cyclodextrins ("CD") may be found in the increased solubility of drug-cyclodextrin complexes in water, thus improving the bioavailability of the drug. See D. Duchene, et al. "Physicochemical characteristics and Pharmaceutical Uses of Cyclodextrin Derivatives Part II," Pharmaceutical Technology (August 1990) p. 22.; J Szejtli, "Cyclodextrins in Drug Formulations: Part II," Pharmaceutical Technology (August 1991) p. 24-30.
It is known, therefore, that CD complexes of hydrophobic drugs in solid dosage form offer improved drug stability resulting in longer shelf life. Lipophilic drugs, in CD complexed form, show increased bioavailability compared to the non-complexed or free forms while reducing local irritation and time for solubilization of the drugs. But CD complexation is not always so advantageous.
On the contrary, certain .beta. and .gamma. cyclodextrins have been found to have an accelerating effect on the rate of degeneration of certain .beta.-lactam antibiotics (T. Loftsson et. al. 1991, International J. Pharmaceutics 67 R5-R7). In addition, the lactamization rate (intramolecular aminolysis) of aqueous solutions of gabapentin (a GABA-derivative) was accelerated in the presence of HP.beta.CD and other types of cyclodextrins. None of the various cyclodextrins thus investigated appeared to stabilize gabapentin.
Hydroxypropyl .beta.-cyclodextrin (HP.beta.CD) has been reported as useful in parental formulations of alfasalone, carbonazepine, and dexamethasone. In addition, delivery systems of gonadal steroids and steroid derivatives using HP.beta.CD complexes have been studied in animals.
In view of the conflicting evidence from the literature in this field, therefore, the effect of the interaction of the CD moieties with alkaloid methyloximes such as CI-979 HCl in solid formulations has been unpredictable. In fact, CD complexation of numerous drugs has been studied over a number of years but only a few drug-CD complexes resulted in advantageous or useful medical products in terms of enhanced stability, bioavailability, or dosage of the drug.
It is therefore the object of the present invention to provide a solid composition for stabilizing certain alkaloid methyloximes, such as the cognition activating agent, CI-979 HCl. In particular, it is the object of the present invention to provide a solid neutral excipient such as polycyclodextrose which simultaneously avoids hydrolytic degradation and neutral/base volatilization of the alkaloid drug.